2-Halopropionic acid and its derivatives

ABSTRACT

Compounds of the formula: ##STR1## wherein R 1  represents hydrogen, lower alkyl having 1 to 5 carbon atoms, halogen, hydroxyl, lower alkoxy having 1 to 4 carbon atoms or trifluoromethyl; R 2  and R 3  are the same or different and each represents hydrogen or a lower alkyl having 1 to 5 carbon atoms; Y represents an alkylenethio group having 1 to 6 carbon atoms, alkyleneoxy having 1 to 6 carbon atoms, or alkylenedioxy having 1 to 6 carbon atoms; Z represents a carboxyl group or a group convertible to carboxyl and n is 1 or 2. The compounds have utility in treatment of hyperlipemia and diabetes.

This is a continuation-in-part of Ser. No. 531,747 filed Dec. 11, 1974,now abandoned.

The present invention relates to a novel compound of the followinggeneral formula (I): ##STR2## wherein R¹ represents hydrogen atom, loweralkyl having 1 to 5 carbon atoms, halogen, hydroxyl, lower alkoxy having1 to 4 carbon atoms or trifluoromethyl; R² and R³ are the same ordifference and each represents hydrogen or a lower alkyl having 1 to 5carbon atoms; Y represent an alkylenethio group having 1 to 6 carbonatoms, an alkyleneoxy group having 1 to 6 carbon atoms or analkylenedioxy group having 1 to 6 carbon atoms; Z represents carboxyl ora group convertible to a carboxyl; n is 1 or 2.

The present inventors have made extensive studies on a series of2-halopropionic acid and its derivatives and succeeded in synthesizingthe novel compound of the above formula (I), and have found that theabove compounds have remarkable hypolipidemic, hypoglycemic and otherbiological activities.

French Pat. No. 2,150,778 discloses in Example 14 the compoundα-bromo-β-(p-benzyloxy)phenylpropionic acid as a chemical intermediate.However, no other utility is disclosed. Moreover, this compound has beentested and has been found inferior with the corresponding 2-chlorocompound of the present invention in hypolipidemic activity. Similarresults have been obtained for other bromo analogs of the present2-chloro compounds.

Netherlands application No. 7,117,006 discloses variousα-halophenoxyphenylacetic acid derivatives with anti-inflammatoryactivity and these are structurally remote from the present compounds.

The principal object of this invention is to provide novel chlorocompounds of the formula (I) useful as medicines such as remedies forhyperlipemia.

Another object of this invention is to provide methods for theproduction of these novel compounds.

Further objects will be made apparent from the description and claimshereinafter given.

The lower alkyl group having 1 to 5 carbon atoms represented by R¹, R²and R³ may be straight or branched and is exemplified by methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl or the like. The halogen atom represented by R¹ isenumerated by chlorine, bromine, iodine and fluorine. The alkoxy grouphaving 1 to 4 carbon atoms represented by R¹ is exemplified by methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy. Thealkyleneoxy group having 1 to 6 carbon atoms represented by Y may bestraight or branched and is exemplified by ##STR3## The alkylenedioxygroup having 1 to 6 carbon atoms represented by Y may be straight orbranched and is exemplified by methylenedioxy (--O--CH₂ --O--),ethylenedioxy ##STR4##

The alkylenethio group having 1 to 6 carbon atoms represented by Y maybe straight or branched and is exemplified by methylenethio (--CH₂--S--), ethylenethio ##STR5## As the group convertible to carboxylgroup, represented by Z, there are exemplified by formyl group, cyanogroup, aminocarbonyl group, an alkoxycarbonyl group having 2 to 5 carbonatoms (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,i-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl), a mono- ordi-alkylaminocarbonyl group having 2 to 9 carbon atoms (e.g.N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-ethylaminocarbonyl,N,N-diethylaminocarbonyl, N-n-propylaminocarbonyl,N,N-di-n-propylaminocarbonyl, N-isopropylaminocarbonyl,N,N-diisopropylaminocarbonyl, N-n-butylaminocarbonyl,N,N-di-n-butylaminocarbonyl), mono- or di-cycloalkylaminocarbonyl having6 to 13 carbon atoms (e.g. N-cyclopentylaminocarbonyl,N,N-dicyclopentylaminocarbonyl, N-cyclohexylaminocarbonyl,N,N-dicyclohexylaminocarbonyl), mono- or diarylaminocarbonyl having 7 to16 carbon atoms (e.g. N-phenylaminocarbonyl, N,N-diphenylaminocarbonyl,N-tolylaminocarbonyl, N,N-ditolylaminocarbonyl). The compound (I)wherein Z is carboxyl group includes pharmaceutically acceptable saltsthereof. As the pharmaceutically acceptable salts, there are exemplifiedby a salt of carboxylic acid with nontoxic cations (e.g. sodium,potassium, lithium, calcium, magnesium, ammonium etc.) or with organicamines such as polyhydroxyalkylamines (e.g. N-methylglucamine,diethanolamine, triethanolamine, trishydroxymethylaminomethane).

The compounds of general formula (I) have prominent hypolipidemic andhypoglycemic activity and show low toxicity and side effect. Takingadvantage of these properties these compounds can safely be used asremedies for hyperlipemia and diabetes in mammals including humanbeings. When a compound (I) is used as such as medicine, it can beadministered, either as it is or in admixture with a pharmaceuticallyacceptable vehicle, excipient or/and diluent, orally or parenterally invarious dosage forms such as powders, granules, tablets, capsules,suppositories and injections. When any of the compounds is used for thepurpose of treating hyperlipemia, it may be administered orally ornon-orally in amounts of 0.03 - 1.0 g. per day for a human adult. Whenany of the compounds is used for the purpose of treating diabetes, itmay be administered orally or non-orally in amounts of 0.1 - 3.0 g. perday for a human adult.

The compounds of formula (I) can be prepared by reacting a diazoniumsalt of formula (II): ##STR6## wherein R¹, Y and n have the samemeanings as given above, with an ethylene compound of the generalformula (III): acetonitrile,

    R.sup.2 CH ═ CR.sup.3 -Z

wherein R², R³ and Z have the same meanings as given above.

This reaction is conducted with advantage in a slight molecular excessof ethylene compound (III) relative to diazonium salt (II). The reactionis commonly carried out in a solvent. As the solvent, there areexemplified water, methanol, ethanol, n-propanol, acetone, methyl ethylketone, diethyl ketone, ethyl propyl ketone, acctonitrile,N-methylpyrrolidone, dimethylsulfoxide, sulfolane, etc. as well asmixtures of such solvents. This reaction is conducted with moreadvantage by adding hydrochloric acid to the reaction system. When asolvent containing hydrochloric acid is used, diazonium salts (II) otherthan the chloride can be employed as a starting material in thisinvention. Moreover, this reaction may be accelerated with advantage byusing a catalyst. As the catalyst, copper compounds, for instance, maybe employed. Thus, cuprous oxide, cupric oxide, cuprous chloride, cupricchloride, cuprous bromide, cupric bromide, copper nitrate, coppersulfate, etc. are more commonly employed. Among them, use of cuprousoxide is the most preferable. The proportion of the catalyst isordinarily 0.02 to 0.2, preferably 0.05 to 0.1, mole per mole ofdiazonium salt (II). To control the reaction velocity, theabove-mentioned catalyst may be used in an increased amount or in areduced amount. The temperature, time, pressure and other conditions ofthe reaction are selected according to the particular startingmaterials, solvent and catalyst and so on. Ordinarily the reactionproceeds smoothly at a temperature under cooling with ice to roomtemperature.

When Z in compound thus obtained is a carboxyl group, it may beconverted by a per se known manner to a pharmaceutically acceptable saltof carboxyl group with a nontoxic cation or with a organic amine whichare mentioned hereinbefore or to an ester such as methyl ester, ethylester, n-propyl ester, isopropyl ester. When Z in compound (I) is agroup convertible to carboxyl group, the group may be converted to acarboxyl group in a per se known manner. When Z is a cyano group, analkoxycarbonyl group or an aminocarbonyl group which is substituted orunsubstituted, it can be converted to a carboxyl group by means ofhydrolysis, whereas when Z is formyl group, it can be oxidized to acarboxyl group. When Z is cyano group, it can also be converted to aminocarbonyl group. For instance, the hydrolysis may be offected by treatingthe compound (I) with such an acid as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid or carbonic acid or with such a base assodium hydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate. In this reaction, such an alcohol as methanol or ethanol maybe allowed to be present as required. The oxidation of the formyl groupcan be accomplished by permitting an oxidation agent to act upon thecompound (I) in a suitable solvent. Examples of said oxidizing agentinclude potassium dichromate, potassium chromate, potassiumpermanganate, hydrogen peroxide, barium peroxide, peracetic acid,perbenzoic acid, hypochlorous acid and ozone. The temperature, time andother conditions of the above-mentioned hydrolysis and oxidationreaction are selected according to such factors as the desired compound(I), solvent and procedure followed.

The compound (I) thus obtained may be separated and purified by per seknown separation-purification procedure such as crystallization,recrystallization, concentration, distillation, chromatography, etc.

The starting material diazonium salt (II) can be prepared by diazotizingthe corresponding amino compound in the presence of hydrochloric acid ina conventional manner or by oringing a diazonium salt (II) wherein Cl isan anion other than halogen into contact with hydrochloric acid.

Throughout the present specification, the abbreviations "mg.", "g.","ml.", "m.p.", "b.p." and "° C", respectively refer to "milligram(s)","gram(s)", "milliliter(s)", "melting point", "boiling point" and"degree(s) centigrade".

REFERENCE EXAMPLE 1

In 120 ml. of ethanol is dissolved 31.2 g. of phenol to which are added24 g. of a methanol solution containing 28% of sodium methoxide and 0.3g. of potassium iodide. Then 20 g. of 4-(2-bromoethyl)acetanilide isadded to the mixture, and the mixture is refluxed for 3.5 hours. Afterthe solvent is distilled off, an aqueous solution of sodium hydroxide in200 ml. of water is added to the residue, and cyrstals formed arecollected by filtration. Recrystallization from ethyl acetate gives 12g. of 4-(2-phenoxyethyl)acetanilide, melting at 121°-123° C.

To a mixed solution of 30 ml. of hydrochloric acid and 20 ml. of wateris added 10 g. of 4-(2-phenoxyethyl)acetanilide and the mixture isrefluxed for 2 hours. After cooling, crystals formed are collected byfiltration. Recrystallization from water gives 7.5 g. of4-(2-phenoxyethyl) aniline hydrochloride, melting at 189°-191° C.

REFERENCE EXAMPLE 2

A mixture of 37.8 g. of 1-phenyl-1-bromo-2-methylpropane, 23.6 g. ofp-nitrophenol, 150 ml. of ethanol and 9.5 g of sodium methoxide isrefluxed for 5 hours. After the reaction has been completed, ethanol isdistilled off and the residue is subjected to extraction with ether. Theextract is washed with 5% aqueous solution of sodium hydroxide and thenwith water. After drying with magnesium sulfate, the solvent isdistilled off. Thus-obtained red oily substance of crude1-phenyl-1-(4-nitrophenoxy)-2-methylpropane is dissolved in 100 ml. ofmethanol, and subjected to catalytic reduction using palladium-carbon.After the reduction has been completed, the catalyst is removed byfiltration. The oily substance obtained by removing the solvent isdissolved in 50 ml. of ether, and concentrated hydrochloric acid isadded to the solution to give 4-(1-phenyl-2-methylpropyloxy) anilinehydrochloride, melting at 165°-168° C.

REFERENCE EXAMPLE 3

A mixture of 240 g of p-chlorobenzyl chloride, 240 g. ofp-acetaminophenol, 850 ml. of ethanol and 290 g. of a 28% methanolicsolution of sodium methoxide is stirred under heating over a mantleheater. The reaction begins abruptly in the neighborhood of 65° C andthe mixture starts undergoing a vigorous reflux. (The mantle heater isremoved.) The reaction mixture is refluxed for 2.5 hours, after whichabout 700 ml. of the solvent is distilled off. The residue is poured inone liter of a 4% aqueous solution of NaOH (containing ice) and theresultant precipitate 4-acetaminophenoxy-4-chlorophenylmethane (whitecrystals) is collected by filtration.

The white crystals obtained in above procudure are not dried but aredirectly dissolved in 1.5 kg. of n-propanol and, after the addition of120 g. of NaOH granules, the solution is refluxed under stirring for 5hours. After the reaction has been completed, the mixture isconcentrated under reduced pressure to remove about 600 ml. of thesolvent and, under stirring, 2 kg. of ice-water is added. The resultantprecipitate 4-(4-chlorobenzyloxy)aniline (brown granules) is collectedby filtration and washed with water. Yield 324 g. Melting point: 102° C.

REFERENCE EXAMPLE 4

In 500 ml. of methanol is dissolved 25 g. of4-(4-chlorophenoxymethyl)nitrobenzene and, with the addition of Raneynickel, the solution was shaken in hydrogen streams. A total of 2.5 ml.of hydrogen is absorbed. The Raney nickel is filtered off and thefiltrate is concentrated to about 40 ml. The resultant crystals arecollected by filtration. The procedure yields 3.5 g. of4-(4-chlorophenoxymethyl)aniline, melting at 125°-126° C.

EXAMPLE 1-(1)

In 500 ml. of acetone is dissolved 94 g. of 4-(4-chlorobenzyloxy)anilineand, at room temperature, a mixture of 200 g. of hydrochloric acid and100 g. of water is added. The solution is cooled well with ice. Whilethe solution is stirred, a solution of 30.8 g. of sodium nitrite in 100ml. of water, then 100 g. of ethyl acrylate and, finally, 5.8 g. ofpowdery cuprous oxide are added. Nitrogen gas is evolved in smallincrements. The ice bath is removed after 10 minutes and, at 12° C, 5.8g. of cuprous oxide is further added. With the evolution of nitrogen gasat a moderate rate, the temperature increases gradually. The mixture isstirred at room temperature for 7 hours. After the reaction has beencompleted, the reaction mixture is concentrated under reduced pressureand extracted with ethyl acetate. The ethyl acetate is distilled off andthe residual red-colored oil is purified by chromatography on silicagel. The described procedure yields 70 g. of ethyl2-chloro-3-(4-(4-chlorobenzyloxy)phenyl)propionate as a yellowish oilyproduct. Cyclohexane/benzene is used as the eluant solvent (First 1:1and then 1:4).

NMR spectrum(δ ppm, CCl₄):

1.17(3H, t), 3.01 - 3.21(2H, m), 4.08(2H, q), 4.23 (1H, t), 4.89(2H, s),6.74(2H, d), 7.02(2H, d), 7.22(4H, s)

EXAMPLES 1-(2) - 1-(37)

By a similar manner to Example 1-(1), the following compounds areproduced.

    ______________________________________                              Starting    Example            Produced-compound compounds    ______________________________________           2-chloro-3-(4-(4-chloro-                              4-(4-chloro-           benzyloxy)phenyl)- benzyloxy)-    1-(2)  propionic acid     aniline,acrylic           m.p.119-121° C                              acid           ethyl 2-chloro-5-(4-           (2-chlorobenzyloxy)-    1-(3)  phenyl)propionate  1-(2-chloro-           yellow oily substance                              benzyloxy)           NMR spectrum (δppm,CDCl.sub.3)                              aniline,ethyl           1.16(3H,t),3.07-3.26                              acrylate           (2H,m),4.13(2H,q),1.38           (1H,t),5.07(2H,s),6.79-           7.60(8H,m)           ethyl 2-chloro-3-(1-(4-           methylbenzyloxy)phenyl)-           propionate         4-(4-methyl-           m.p.20-24° C                              benzyloxy)-    1-(4)  NMR spectrum(δppm.CDCl.sub.3)                              aniline,ethyl           1.22(3H,t),2.37(2H,s),                              acrylate           3.23(2H,m),4.20(2H,q),           4.40(1H,t),5.02(2H,s),           6.74-7.54(8H,m)           ethyl 2-chloro-3-(1-(4-           methoxybenzyloxy)-           phenyl)propionate  4-(4-methoxy-    1-(5)  NMR spectrum(δppm,CDCl.sub.3)                              benzyloxy)-           1.13(3H,t),3.15(2H,m),                              aniline,ethyl           3.68(3H,s),4.10(2H,q),                              acrylate           4.35(1H,t),4.86(2H,s),           6.7-7.5(8H,m)           ethyl 2-chloro-3-(4-           benzyloxyphenyl)-           propionate           yellow oily substance                              4-benzyloxy-    1-(6)  NMR spectrum(δppm,CDCl.sub.4)                              aniline,ethyl           1.12(3H,t),3.00-3.22                              acrylate           (2H,m),4.06(2H,q),           4.25(1H,t),4.90(2H,s),           6.80(2H,d),7.01(2H,d),           7.27(5H,s)           methyl 2-chloro-2-methyl-           3-(4-(2-fluorobenzyloxy)-           phenyl)propionate  4-(2-fluoro-    1-(7)  yellow oil         benzyloxy)-           NMR spectrum (δppm,CDCl.sub.3)                              aniline,methyl           1.6(3H,s),3.3(2H,s),                              methacrylate           3.7(3H,s),5.1(2H,s),           7.2(8H,m)           ethyl 2-chloro-3-(4-(2-           phenylethyloxy)phenyl)-                              4-(2-phenyl-           propionate         ethyloxy)    1-(8)  yellow oily substance                              aniline,ethyl           NMR spectrum(δppm,CDCl.sub.3)                              acrylate           1.2(3H,t),3.2(4H,m),           4.2(5H,m),6.8(2H,d),           7.1(2H,d),7.25(5H,s)           methyl 2-chloro-3-(4-(2-           phenylethyloxy)phenyl)-                              4-(2-phenyl-    1-(9)  propionate         ethyloxy)-           red oily substance aniline,methyl           IR spectrum(cm.sup.-1,                              acrylate           1740,1605,1505,1240,           1015,750,700           ethyl 2-chloro-3-{4-(2-           (4-chlorophenoxy)- 4-(2-(4-chloro-    1-(10) ethyloxy!phenyl-   phenoxy)ethyloxy!-           propionate         aniline,ethyl           needles m.p.81-82° C                              acrylate           ethyl 2-chloro-3-(4-(4-           chlorophenoxymethyl)-           phenyl)propionate           NMR spectrum(δppm,CDCl.sub.3)                              4-(4-chloro-    1-(11) 1.20(3H,t),3.22(2H,m),                              phenoxymethyl)-           4.07(2H,q),4.43(1H,t),                              aniline,ethyl           4.97(2H,s),6.7-7.5 acrylate           (8H,m)           2-chloro-3-(4-benzyloxy-                              4-benzyloxy-    1-(12) phenyl)propionamide                              aniline           m.p.134-135° C                              acrylamide           2-chloro-3-(4-(2-  4-(2-phenyl-    1-(13) phenylethyloxy)phenyl)-                              ethyloxy)-           propionamide       aniline           m.p.101° C  acrylamide           ethyl 2-chloro-3-(4-(3-           phenylpropyloxy)phenyl)-           propionate         4-(3-phenyl-           oily substance     propyloxy)-    1-(14) NMR spectrum(δppm,CDCl.sub.3)                              aniline           1.20(3H,t),2.09(2H,m),                              ethyl           2.80(2H,t),3.20(2H,m),                              acrylate           3.93(2H,t),4.18(2H,q),           4.39(1H,t),6.80(2H,d),           7.10(2H,d),7.20(5H,s)           ethyl 2-chloro-3-(4-(4-           phenylbutyloxy)phenyl!-           propionate           yellow oily substance                              4-(4-phenyl-    1-(15) NMR spectrum(δppm,CDCl.sub.3)                              buthyloxy-           1.17(3H,t),1.73(4H,m),                              aniline,ethyl           2.63(2H,t),3.15(2H,m),                              acrylate           3.87(2H,t),4.10(2H,q),           4.33(1H,t),6.7-7.4           (9H,m)           ethyl 2-chloro-3-(4-           benzylthiophenyl)-           propionate         4-benzylthio-           oily substance     aniline hydro-    1-(16) NMR spectrum(δppm,CDCl.sub.3)                              chloride           1.20(3H,t),3.20(2H,m),                              ethyl           4.09(2H,s),4.18(2H,q),                              acrylate           4.40(1H,t),6.90-7.60           (9H,m)           ethyl 2-chloro-3-(4-(4-           fluorobenzyloxy)phenyl)-           propionate         4-(4-fluoro-    1-(17) NMR spectrum(δppm,CDCl.sub.3)                              benzyloxy)-           1.09(3H,t),3.15(2H,m),                              aniline,ethyl           4.06(2H,q),4.35(1H,t),                              acrylate           4.83(2H,s),6.7-7.5           (8H,m)           ethyl 2-chloro-3-(4-(3-           fluorobenzyloxy)phenyl)-           propionate         4-(3-fluoro-           oily substance     benzyloxy)-    1-(18) NMR spectrum(δppm,CDCl.sub.3)                              aniline           1.17(3H,t),3.19(2H,m),                              hydrochloride           4.13(2H,q),4.36(1H,t),                              ethyl           4.97(2H,s),6.67-7.53                              acrylate           (8H,m)           ethyl 2-chloro-3-(4-(2-           fluorobenzyloxy)phenyl)-           propionate           yellow oily substance                              4-(2-fluoro-    1-(19) NMR spectrum(δppm,CDCl.sub.3)                              benzyloxy)-           1.19(3H,t),2.87-3.53                              aniline,ethyl           (2H,m),4.16(2H,q), acrylate           4.39(1H,t),5.08(2H,s),           6.82-7.62(8H,m)           2-chloro-3-(4-(3-chloro-                              4-(3-chloro-           benzyloxy)phenyl)pro-                              benzyloxy)-    1-(20) pionic acid        aniline           m.p.88-89° C                              acrylic acid           ethyl 2-chloro-3- 4-(3-           trifluoromethylbenzyloxy)-           phenyl)propionate  4-(3-trifluoro-           oily substance     methylbenzyloxy)-    1-(21) NMR spectrum(δppm,CDCl.sub.3)                              aniline,ethyl           1.20(3H,t),3.20(2H,m),                              acrylate           3.80-4.60(3H,m),5.05           (2H,s),6.70-7.90(8H,m)           N-phenyl-2-chloro-3-(4-                              4-(4-chloro-           (4-chlorobenzyloxy)-                              benzyloxy)-    1-(22) phenyl)propionamide                              aniline,           white crystal      N-phenyl-           m.p.177-178° C                              acrylamide           N-isopropyl-2-chloro-3-                              4-(2-phenyl-           (4-(2-phenylethyloxy)-                              ethyloxy)-    1-(23) phenyl)propionamide                              aniline,           white crystal      N-isopropyl-           m.p.98-99° C                              acrylamide           N-methyl-N-(n-butyl)-2-           chloro-3-(4-(2-phenyl-           ethyloxy)phenyl)-           propionamide       4-(2-phenyl-           oily substance     ethyloxy)-    1-(24) NMR spectrum(δppm,CDCl.sub.4)                              aniline           0.91(3H,t),1.33(4H,or),                              N-methyl-N-           2.84(3H,d),3.09(2H,t),                              (n-butyl)-           3.27(2H,t),2.80-3.63(2H,                              acrylamide           m),4.08(2H,t),4.33-4.56           (1H,m),6.73(2H,d),7.07           (2H,d),7.16(5H,c)           ethyl 2-chloro-3-(4-           phenoxymethylphenyl)-           propionate         4-phenoxy-    1-(25) NMR spectrum(δppm,CDCl.sub.3)                              methylaniline           1.17(3H,t),3.21(2H,m),                              ethyl           4.11(2H,q),4.40(1H,t),                              acrylate           4.97(2H,s),6.7-7.5           (5H,m)           ethyl 2-chloro-3-(4-(1-           phenylethyloxy)phenyl)-           propionate           yellow oily substance                              4-(1-phenyl-    1-(26) NMR spectrum(δppm,CDCl.sub.3)                              ethyloxy)-           1.10(3H,t),1.58(3H,d),                              aniline           2.79-3.43(2H,m),4.07                              ethyl           (2H,q),4.30(1H,t), acrylate           5.23(1H,q),6.77(2H,d),           6.96(2H,d),7.23(5H,s)           ethyl 2-chloro-3-(4-(2-                              4-(2-phenoxy-    1-(27) phenoxyethyloxy)phenyl!-                              ethyloxy)aniline           propionate         ethyl acrylate           m.p.80-81° C           ethyl 2-chloro-3-(4-(1-           phenylpropyloxy)phenyl)-           propionate           yellow oily substance           NMR spectrum(δppm,CDCl.sub.3)                              4-(1-phenyl-    1-(28) 0.93(3H,t),1.09(3H,t),                              propyloxy)-           1.83(2H,q),2.77-3.49                              aniline           (2H,m),4.07(2H,q), ethyl           4.29(1H,t),4.95(1H,t),                              acrylate           6.76(2H,d),6.97(2H,d),           7.23(5H,s)           ethyl 2-chloro-3-(4-(1-           phenylbutyloxy)phenyl)-           propionate           yellow oily substance           NMR spectrum(δppm,CDCl.sub.3)                              4-(1-phenyl-    1-(29) 0.77-2.13(7H,m),1.13(3H,                              butyloxy)-           t),2.78-3.43(2H,m),                              aniline           4.08(2H,q),4.33(1H,t),                              ethyl           5.05(1H,t),6.76(2H,d),                              acrylate           6.96(2H,d),7.26(5H,s)           ethyl 2-chloro-3-(4-(1-           phenyl-2-methylpropyloxy)-           phenyl)propionate           yellow oily substance                              4-(1-phenyl-    1-(30) NMR Spectrum(δppm, CDCl.sub.3)                              2-methyl-           0.85-1.29(9H,m),1.87-                              propyloxy)-           2.43(1H,m), 2.79-3.47                              aniline           (2H,m), 4.11(2H,q), 4,35                              ethyl           (1H,t),4.77(1H,d),6.76                              acrylate           (2H,d),7.00(2H,d),           7.27(5H,s)           ethyl 2-chloro-3-(4-(1-           phenylpentyloxy)phenyl)-           propionate         4-(1-phenyl-           oily substance     pentyloxy)-    1-(31) NMR spectrum(δppm, CDCl.sub.3)                              aniline           0.67-2.30(12H,m),3.10                              ethyl           (2H,m),4.17(2H,m), acrylate           4.37(1H,t),5.08(1H,t),           6.90(4H,q),7.30(5H,s)           ethyl 2-chloro-3-(4-(1-           phenoxyethyl)phenyl)-           propionate         4-(1-phenoxy-    1-(32) NMR spectrum(δppm,CDCl.sub.3)                              ethyl)aniline           1.12(3H,t), 1.56(3H,d),                              ethyl           3.16(2H,m),4.08(2H,q),                              acrylate           4.38(1H,t),5.21(1H,q),           6.67-7.4(9H,m)     7.4(9H,m)           ethyl 2-choro-3-(4-(1-           methyl-2-phenylethyloxy)-           phenyl)propionate           oily substance     4-(1-methyl-    1-(33) NMR spectrum(δppm,CDCl.sub.3)                              2-phenyl-           1.17(3H,t),1.20(3H,d),                              ethyloxy)-           2.90(4H,m),4.13(2H,q),                              aniline           4.33(1H,t),4.46(1H,m),                              ethyl           6.77(2H,d),7.07(2H,d),                              acrylate           7.17(5H,s)           2-chloro-3-(4-(1-           phenylethyloxy)phenyl)-           propionamide       4-(1-phenyl-           brown oil substance                              ethyloxy)aniline    1-(34) NMR spectrum(δppm,CDCl.sub.3)                              acrylamide           1.59(3H,d),2.80-3.50           (2H,m),4.26-4.47(1H,m),           5.26(1H,q),6.43(2H,br),           6.80(2H,d),7.04(2H,d),           7.31(5H,d)           N-phenyl-2-chloro-3-(4-                              4-(1-phenyl-    1-(35) (1-phenylethyloxy)phenyl)-                              ethyloxy)-           propionamide       aniline           m.p.90-91° C                              M-phenyl                              acrylamide           2-chloro-3-(4-(1-           phenylethyloxy)phenyl)-           propionic acid     4-(1-phenyl-           colorless oily substance                              ethyloxy)-    1-(36) NMR spectrum(δppm,CDCl.sub.1)                              aniline           1.57(3H,d),3.10(2H,m)                              acrylic acid           4.27(1H,t),5.17(1H,Q),           6.70(2H,d),6.97(2H,d),           7.20(5H,s),11.53(1H,s).           2-chloro-3-(4-(1-           phenylethyloxy)phenyl)-           propionic acid     4-(1-phenyl-           yellow oily substance                              propyloxy)-    1-(37) NMR spectrum(δppm,CDCl.sub.3)                              aniline           0.97(3H,t),1.90(2H,m),                              acrylic acid           3.10(2H,m),4.33(1H,t),           4.97(1H,t),6.75(2H,d),           7.03(2H,d),7.23(5H,s),           8.67(1H,s)    ______________________________________

EXAMPLE 2-(1)

In 40 ml. of methanol is dissolved 5.0 g. of ethyl 2-chloro-3-4-(4-chlorobenzyloxy)phenyl!propionate, and 6.0 g. of a 20% aqueoussolution of sodium hydroxide is added. The mixture is stirred at roomtemperature for 3 hours and the resultant white crystals are collectedby filtration and washed with ether. The procedure yields 3.9 g. ofsodium 2-chloro-3- 4-(4-chlorobenzyloxy)phenyl!propionate, monohydrateas white crystals melting at 218°- 221° C.

EXAMPLES 2-(2) - 2-(4)

By a similar manner to Example 2-(1), the following salts are producedfrom the corresponding esters.

    ______________________________________    Example             Produced salt    ______________________________________    2-(2)  sodium 2-chloro-3-(4-benzyloxyphenyl)-           propionated-monohydrate           m.p. 214-216° C    2-(3)  sodium 2-chloro-3- 4-(1-phenylethoxy)-           phenyl!propionate-monohydrate           m.p. 171-174° C    2-(4)  sodium 2-chloro-3 4-(1-phenylpropyloxy)-           phenyl!propionate           m.p. 183-184° C    ______________________________________

EXAMPLE 3-(1)

In 60 ml. of acetone is dissolved 7.5 g. of 4-(2-phenoxyethyl)anilinehydrochloride, followed by the addition of 7.5 ml. of hydrochloric acid,the mixture is kept at not higher than 10° C. Under stirring, a solutionof 2.3 g. sodium nitrite in 4.5 ml. water is added, and the mixture iskept at the same temperature for 30 minutes. To the mixture, 25 ml. oftheyl acrylate is added and under stirring, cuprous oxide is added insmall portions until evolution of gas has ceased. The mixture issubjected to extraction with ether and the extract is washed three timeswith water, and then the solvent is distilled off. The residue isdissolved in 70 ml. of ethanol, and under stirring and ice cooling, asolution of 1.2 g. of sodium hydroxide in 4 ml. water is added. Afterone hour, the resultant crystals are collected by filtration and dried.Recrystallization from ligroine gives 4.5 g. of 2-chloro-3-4-(2-phenoxyethyl)phenyl!propionic acid. Melting point: 97°- 99° C.

EXAMPLE 4-(1)

In 40 ml. of methanol is dissolved 6.6 g. of ethyl 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionate, and under cooling with ice andstirring, a solution of 0.8 g. sodium hydroxide in 1.2 ml. water isadded. The mixture is kept under the same condition for 3 hours, afterwhich the solution is neutralized with acetic acid. Then the solution isconcentrated to dryness. The residue is washed well with cyclohexane anddissolved in water. After treating with activated carbon, the solutionis acidified with hydrochloric acid. The resultant oily substance isextracted with chloroform and the chloroform is distilled off to give 4g. of 2-chloro-3- 4-(1-phenylethyloxy)phenyl!propionic acid as acolorless oily substance.

NMR spectrum (δ ppm, CCl₄)

1.57(3H,d), 3.10(2H,M), 4.27(1H,t), 5.17(1H,q), 6.70(2H,d), 6.97(2H,d),7.20(5H,s), 11.53(1H,s).

EXAMPLE 5-(1)

In 40 ml. of ethanol is dissolved 1.46 g. of 2-chloro-3-4-(4-chlorobenzyloxy)phenyl!propionic acid, followed by the addition of0.25 g. of potassium hydroxide. The mixture is stirred at roomtemperature for 1 hour and the resultant crystals are collected byfiltration. These crystals are recrystallized from water to obtain 1.2g. of potassium 2-chloro-3- 4-(4-chlorobenzyloxy)phenyl!propionate,melting point: 161°-162° C.

EXAMPLE 6-(1)

In 40 ml. of acetone is dissolved 5.3 g. of 4-(3-phenoxypropyl)anilinehydrochloride, followed by the addition of 5 ml. of hydrochloric acid,and the mixture is kept at not higher than 10° C. Under stirring, asolution of 1.52 g. of sodium nitrite in 3 ml. water is added and themixture is kept at the same temperature for 30 minutes. To the mixture,16 ml. of acrylic acid is added, and under stirring at 0°-5° C, cuprousoxide is added in small portions until evolution of gas has ceased. Thereaction mixture is concentrated to dryness under reduced pressure. Tothe residue is added diluted hydrochloric acid and the mixture issubjected to extraction with benzene. The benzene layer is washed withwater and an aqueous solution of 2 g. anhydrous sodium carbonate in 100ml. water is added. The resultant crystals are heated to dissolve andthen cooled. The crystals formed are collected by filtration and washedwith a small volume of water and ethanol and dried under reducedpressure. The described procedure gives 4 g. of sodium 2-chloro-3-4-(3-phenoxypropyl)phenyl! propionate. Melting point: 195°-196° C.

EXAMPLE 7-(1)

In 600 ml. of acetone is dissolved 70 g. of4-(3-chlorobenzyloxy)aniline, followed by the addition of 100 ml. ofhydrochloric acid. Under stirring and cooling with ice, a solution of22.8 g. sodium nitrite in a sufficient volume of water to make 45 ml. isslowly added. The mixture is stirred under the same conditions for 30minutes, after which 250 ml. of ethyl acrylate is added. While thisreaction mixture is maintained at 24°-26° C, cuprous oxide is added insmall portions until the evolution of gas has ceased. Then, 200 ml. ofether is added and the organic layer is washed three times with water.The solvent is thoroughly distilled off and the residue is dissolved in900 ml. of ethanol. Under cooling with ice and stirring, a solution of15 g. sodium hydroxide in a sufficient water to make 40 ml. is slowlyadded. Thereafter, the mixture is stirred under the same conditions for1.5 hours and the resulting crystals are collected by filtration.Recrystallization from dilute ethanol yields 55 g. of sodium 2-chloro-3-4-(3-chlorobenzyloxy)phenyl!propionate, melting point: 205°-208° C.

EXAMPLE 8-(1)

In 10 ml. of water is dissolved 300 mg. of sodium 2-chloro-3-4-(1-phenylpropyloxy)phenyl!propionate, followed by the addition ofexcess volume of aqueous solution of calcium chloride. The oilysubstance separated out is extracted with a mixture of ether and ethylacetate (1:1). The extract is washed with water and the precipitateformed is filtered off. The solvent is distilled off and the residue issubjected to recrystallization from 4 ml. of 50% aqueous ethanol. Thedescribed procedure gives 150 mg. of calcium 2-chloro-3-4-(1-phenylpropyloxy)phenyl!propionate. Melting point: 145° C

EXAMPLE 9-(1)

In 20 ml. of tetrahydrofuran is dissolved 1.0 g. of 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionic acid. Under cooling and stirring,0.33 g. of triethylamine and then 0.34 g. of ethyl chlorocarbonate areadded dropwise. The resultant white precipitates are filtered off. Tothe filtrate, 0.31 g. of aniline is added dropwise under cooling withice and stirring. The mixture is stirred for about 2 hours. Aftertetrahydrofuran is distilled off, chloroform is added. The chloroformlayer is washed with diluted hydrochloric acid and dried over magnesiumsulfate. After the chloroform is distilled off, the resultant oil ispurified by column chromatography, to give 580 mg. of oil. To this oilis added a mixture of petroleum ether and methanol, and the resultantcrystals are collected by filtration. Recrystallization from petroleumether gives N-phenyl-2-chloro-3-4-(1-phenylethyloxy)phenyl!propionamide. Melting point: 90°-91° C.

EXAMPLES 9-(2) - 9-(3)

By a similar manner to Example 9-(1), the following compounds areproduced.

    ______________________________________    Example             Produced compound    ______________________________________    9-(2)  N-butyl-2-chloro-3- 4-(1-phenylethyloxy-           phenyl!propionamide           oily substance           NMR spectrum (δppm, CDCl.sub.3)           0.78(3H,t), 1.0-1.6(4H,m, 1.62(3H,d),           2.9-3.5(4H,m), 4.45(1H,t), 5.25(1H,q),           6.40(1H,br), 6.6-7.5(9H,m)    9-(3)  N-methyl-N-butyl-2-chloro-3- 4-(1-phenyl-           ethyloxy)phenyl!propionamide           oily substance           NMR spectrum (δppm, CDCl.sub.3)           0.87(3H,t), 1.0-1.5(4H,m), 1.57(3H,d),           2.83(3H,s), 2.8-3.5(4H,m), 4.53(1H,t),           5.27(1H,q), 6.5-7.5(9H,m)    ______________________________________

COMPARATIVE EXAMPLES

To establish the superiority of the chloro compounds of this inventionof the corresponding bromo compounds the following experiment wasperformed.

Experiment

1. Test Compound: ##STR7##

2-bromo-3- 4-(4-chlorobenzyloxy)phenyl!propionic acid

2. Animal employed in the test;

Male SD rats aged 8 to 9 weeks

3. Test method;

Blood lipid lowering effect:

One each of the test compounds was mixed in a laboratory chow purchasedfrom CLEA Japan, Tokyo at a level cited in the table and fed to rats (5rats for each group) for 4 days. Blood was taken from tail vein in themorning of the fifth day and used for the determination of plasmatriglycerides (TG) and total cholesterol (TC).

4. result;

The result is shown in the following Table.

    ______________________________________    Dose           Plasma (mg/100 ml)    Compounds            (% in diet)                        TG           TC    ______________________________________    Control 0          192±36    71±9    (I)     0.02       120±8 *   50±9*    (II)    0.02       191±52    69±8    Control 0          197±32    74±7    (III)   0.01        69±19*   53±6*    (IV)    0.01       157±36    75±8    ______________________________________     (note)     Significance of difference was ascertained with Student's t-test.     *: P<0.02

Conclusion

It is concluded that compound (I) is superior to compound (II) inhypolipidemic activity.

It is also concluded that compound (III) is superior to compound (IV) inhypolipidemic activity.

We claim:
 1. A compound of the formula: ##STR8## wherein R¹ representshydrogen, lower alkyl having 1 to 5 carbon atoms, halogen, hydroxyl,lower alkoxy having 1 to 4 carbon atoms or trifluoromethyl; R² and R³are the same or different and each represents hydrogen or lower alkylhaving 1 to 5 carbon atoms; Y represents alkylenoxy having 1 to 6 carbonatoms or alkylenedioxy having 1 to 6 carbon atoms; Z represents acarboxyl group or group convertible to a carboxyl group which is anaminocarbonyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms,a mono- or di-alkylaminocarbonyl group having 2 to 9 carbon atoms ormono- or di-arylaminocarbonyl group having 7 to 16 carbon atoms and n=1or
 2. 2. A compound as claimed in claim 1, wherein Y is an alkyleneoxygroup having 1 to 6 carbon atoms.
 3. A compound as claimed in claim 1,wherein Y is an alkylenedioxy group having 1 to 6 carbon atoms.
 4. Acompound as claimed in claim 1, wherein R² is hydrogen atom.
 5. Acompound as claimed in claim 1, wherein R² is an alkyl group having 1 to5 carbon atoms.
 6. A compound as claimed in claim 1, wherein R³ ishydrogen atom.
 7. A compound as claimed in claim 1, wherein R³ is analkyl group having 1 to 5 carbon atoms.
 8. A compound as claimed inclaim 1, wherein R¹ is hydrogen atom.
 9. A compound as claimed in claim1, wherein R¹ is a lower alkyl group having 1 to 5 carbon atoms.
 10. Acompound as claimed in claim 1, wherein R¹ is a halogen atom.
 11. Acompound as claimed in claim 1, wherein R¹ is an alkoxy group having 1to 4 carbon atoms.
 12. A compound as claimed in claim 1, wherein Z iscarboxyl group.
 13. A compound as claimed in claim 1, wherein thecompound is 2-chloro-3-(4-benzyloxyphenyl)propionic acid.
 14. A compoundas claimed in claim 1, wherein the compound is2-chloro-3-(4-benzyloxyphenyl)propionamide.
 15. A compound as claimed inclaim 1, wherein the compound is ethyl2-chloro-3-(4-benzyloxyphenyl)propionate.
 16. A compound as claimed inclaim 1, wherein the compound is 2-chloro-3-4-(4-chlorobenzyloxy)phenyl!propionic acid.
 17. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(4-chlorobenzyloxy)phenyl!propionate.
 18. A compound as claimed inclaim 1, wherein the compound is 2-chloro-3-4-(3-chlorobenzyloxy)phenyl!propionic acid.
 19. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(2chlorobenzyloxy)phenyl!propionate.
 20. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(4-fluorobenzyloxy)phenyl!propionate.
 21. A compound as claimed inclaim 1, wherein the compound is 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionic acid.
 22. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionate.
 23. A compound as claimed inclaim 1, wherein the compound is 2-chloro-3-4-(1-phenylpropyloxy)phenyl!propionic acid.
 24. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(1-phenylpropyloxy)phenyl!propionate.
 25. A compound as claimed inclaim 1, wherein the compound is ethyl 2-chloro-3-4-(1-methyl-2-phenylethyloxy) phenyl!-propionate.
 26. A compound asclaimed in claim 1, wherein the compound is ethyl2-chloro-3-(4-phenoxymethylphenyl)propionate.
 27. A compound as claimedin claim 1, wherein the compound is ethyl 2-chloro-3-4-(1-phenoxyethyl)phenyl!propionate.
 28. A compound as claimed in claim1, wherein Z is a pharmaceutically acceptable salt of carboxyl.
 29. Acompound as claimed in claim 1, which is sodium 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionate.
 30. A compound as claimed inclaim 1, which is sodium 2-chloro-3-4-(1-phenylethyloxy)phenyl!propionatemonohydrate.